DESCRIPTION Intraperitoneal (ip) injection of lipopolysaccharide (LPS) results in an acute phase response (APR), which includes the development of fever. As a result of recent work from several laboratories, evidence has accumulated that an ip injection of LPS induces fever by causing the release into the circulation of an endogenous pyrogen (EP), possibly interleukin-1 (IL-1), which in turn causes a rise in hypothalamic interleukin-6 (IL-6). Although there are data showing that tumor necrosis factor (TNF) is a pyrogen, most of these studies were based on injection of pharmacological doses of this cytokine. Using neutralizing antibodies or soluble receptors to TNF, Dr. Kluger has generated data showing that TNF might actually be an endogenous cryogen (EC), which limits fever. The purpose of the proposed experiments is to continue our investigations to critically evaluate the degree to which LPS-and bacterial-induced fevers actually involve these and other cytokines both in the circulation and the brain. We hypothesize that some of these cytokines are endogenous pyrogens and others are endogenous antipyretics or cryogens. The balance between the two types of mediators determines the pattern and time-course of fever. Our specific aims are to continue our studies to investigate: the pyrogenic effects of IL-1, the relationship between IL-1 and IL-6 in fever, the antipyretic or cryogenic actions of TNF, the possible role of other cytokines as endogenous antipyretics or endogenous cryogens, gender differences in febrile responses. These studies will be run in both male and female rats, and in transgenic knock- out mice deficient in the genes for various cytokines or cytokine receptors. One of the difficulties in studying the precise roles of cytokines in fever has been the inability to selectively block the biological actions of specific cytokines. With the advent of recombinant cytokines, the development of antibodies and other specific blockers, and the availability of transgenic knock-out mice, it is now possible to assess the roles of cytokines in the fever.